Paradoxical Reactions in HIV and Pulmonary TB

Antigens The patient's and her husband's sera were tested and co rnpared with two normal control sera. Antigens tested were the humidifier water and fun gal antigens. Aspergillus fu migatus was prepared b y Dr. Viswanath Kurup , Medical College of Wisconsins Thermoactinomycetes vulgaris and Saccaromonospora !Ardis were from the same source. Othe r fungal antigens wereobtained commercially from Bayer Allergy Products, Spokane, W A, and Gree r L aboratories, Lenoir, NC. The most concentrated solution available was used. RESULTS

Serologic Studies Of note is that the patient had l l positive precipitin reactions as follows: Cephalosporium acremonium, S virdis, Cladosporioides, Curvularia spiciferia, Helminthosporium sativum, Paecilomyces variotii, Penicillium mix, A flavus , A lgacus, A nidulans, and humidifier w ater. The serum from the patient was negative for other fungal antigens including A fumigatus. He r husband's serum and control sera were negative for all antigens listed and other fungal antigens and pigeon dropping extract.

Histologic Findings in the Lung Biopsy Tissue sections showed loosely form ed noncaseating granulomas containing Langerhans' giant cells that were numerous both in interstitial tissue and alveoli (Fig 1). There was no evidence of interstitial fibrosis or obliterative bronchiolitis. Results of a high-resolution CT s can of the chest are shown in Figure 2. Lung windows demonstrated extensive a re as of ground-glass opacification throughout both lung fields. There was no evidence of distortion of the lung parenchyma. DISCUSSION

The case presented illustrates the complexity and importance of the diagnosis of HP. The laboratory at the Northweste rn University Allergy-Immunology Service rral laboratory for allergic bronchopulmoserves as a refe nary aspergillosis (ABPA) and HP. Most recently, patie nts have been r eferred to this laboratory for cases of HP, these included persons working with raptors, such as a r pa tor handler who kept a great horned owl in her b edroom. 6 The history of significant bird exposure or occupational exposures, such as in farmers, provides leads for the clinician to look at sources of antigen. In the case of the patient presented h ere, there were no occupational activities or hobbies that would suggest an antigen. The house was immaculate, and the only possible lead was a contaminated humidifier. The serologic responses and clinical improvement after removal of the humidifier were consistent with humidifier disease. The presence o fprecipitating antibody against ten s aprophytic organisms plus the humidifier water is unique in the experience of the authors. Contamination of houses b y sewage water with resultant HP has been reported.7 In some cases of HP due to humidifier water exposure, the antigens were traced to the source of the water (Lake Michigan) but the source of the actual antigens in the water was never identified. 8

A final complication of diagnosing HP or ABPA is that the clinician may suspect the correct diagnosis and the causative antigen in HP or the presence of ABPA, but the serologic studies may not be done appropriately. This is periodically seen in patients whose sera have been s ent to the Northwestern University Allergy-Immunology Service laboratory. Patterson et al. 9 have reported a series of seven cases of HP or ABPA where preliminary serologic examination done elsewhere was incorrect. When the serologic tests were carefully repeated, the correct serologic examinations were consistent with the correct diagnosis.9 A recent publication has reviewed the diagnostic criteria for HP. 10 The histologic changes seen in lung biopsy tissue a re consistent with HP.J REFERENCES

1 S alvaggio JE, Beuchner HA, Seabmy JH , et la. Bagassosis. l . Precipitins against extracts of crude bagassee in th e serum of patients with bagassosis. Ann Intern Med 1996; 64:748-758 2 Pepys J. Hypersensitivity disease of the lungs du e to fungi and other organi c dusts. Monographs in allergy (vol 4). Basel, Switzerl and: S Karger, 1969 3 Fink JN. Hypersensitivity pneumonitis. In: Patterson R, Grammer LG, Greenberger PA, eds. Allergic diseases: di agnosis and manageme nt. 5th ed. Philadelphia: LippincottRaven, 1997; 543-553 4 Crowle AJ. Immunodi ffusion. New York: Academic Press, 1961 .5 Kurup VP, Fink JN, Scribner GH, et la. Antigenic variability of Aspergillus fumi gatus strains. Microbios 1977; 19:191-204 6 Choy AC, Patterson R, Ray AH, et la. Hypersensitivity pneumonitis in a r aptor h andler and a wild bird fan cier. Ann Allergy Asthma Immunol199.5; 74:437-441 7 Patterson R , Fink JN, Miles WB , et al. Hypersensitivity lung disease presumptively due to Cephalosporium in homes flooding or by humidifie r water. J s contaminated b y ewage Allergy Clin Immunol 1981; 68:128-132 8 P atterson R, Fink JN, Roberts M, etal. Antibody activity in sera o f patients v.~ th humidifier disease. J Allergy Clin Immunol 1978; 62:103-108 9 Patterson R, Greenbe rger PA, Castile RG, et !.a Diagnostic problems in hypersensitivity lung disease. Allergy Proc 1989; 10:141-147 10 Schuyler M, Cormier Y . The di agnosis o f hype rs e n siti,~ty pneumonitis. Chest 1 997; 111:534-.536

Paradoxical Reactions in H IV and Pulmonary TB* Jason W. Chien, MD; and John L. Johnson, MD

We present a case of paradoxical clinical deterioration during antituberculosis therapy in an HIVinfected adult with pulmonary TB. The clinical course was characterized by marked cervical and mediastinal adenopathy accompanied by fever and weight loss during simultaneous treatment of TB and HIV disease. After extensive investigation for causes of therapeutic failure, the paradoxical reaction was attributed to partial immune reconstitution related CHEST / 114 / 3 I SEPTEMBER, 1998

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to highly effective antiretroviral therapy. Due to the high prevalence of TB in HIV -infected patients, it is important to recognize this phenomenon and understand that it is usually self-limited. (CHEST 1998; 114:933-936) Key w01·ds: antiretroviral th e rapy; IllV; immune reconstitution ;

lymphadenopathy; Mycohact;erirun tnherculosis ; paradoxical reaction

p aradoxical reactions and de te rioration in patients

bein g treated for TB have bee n w ell-described in non-1-IIV-infected individuals. This phenomenon usually involves new or increasing enlargement of lymph nodes, cerebral tuberculomas, pulmonary in filtrates, or pleural disease. Th ese paradoxical reactions have been attributed to reconstitution of the host immune responses following th e initiation of antituberculosis the rapy. Immnn e reconstitution is also part of the response to highly active antiretroviral th e rapy in 1-IIV-infectcd pati ents. llowever, paradoxical reactions in 1-IIV-infeeted pati ents with TB following th erapy for both diseases have not bee n well described. vVe report one such case he re. CASE REPORT

A 44-year-old [IJV-1-inf'ectcd man presented with a 3-week hi story of fittign e, ano rex ia, and weight loss. Physical examination revealed a te mpe rature of' 40.2°C orally, small shotty bilate ral cetvical nodes, and egophony ove r th e right ante rior midchest. His CD4 lymphocyte co unt was 220/ JJ-L, '~ra lload was > 750,000 HIV H.NA copies/mL, and a c hest radiograph de mon strated a right middl e lobe infiltrate (Fig 1). Sputum smears for acid-fast bacilli were positi ve. Th e patient was started on isoniazid, rihunpin , pyrazinamide, and e thambutol for pres umed TB , and lami vuclin e and stavll(l ine fiJr HlV infection. Sputum cu ltmes subsequ ently g rew pan-sensiti ve Mycohacterittlll tuhercnlosis. Despite 6 weeks of directly obsetved TB th e rapy, th e patie nt continued to have hectic fever and cough with a Further weight loss of I 0 kg. Sputum smea rs for acid-Ltst bacilli were repeatedly positive. Acquired drug resistance, bacterial superinfection , drug reaction, and malabsorption were cxclll(lcd. Smear and cu lture after large-bore needl e asp iration of a new 3-cm finn , non tender left anterior c:eJvic:al node showed no organisms. Hepcat CD4 lymphocyte count was 420/JJ-L. A chest radiograph reveal ed new mediastinal and hilar adenopathy "~th infiltrates (Fig 2). Achest CT scan de monstrated ex ten sive adenopathy surroundin g th e trach ea, carina, and mainste m bronchi. Antitube rculosis and antire tro~ral medications we re co ntinu ed. A tapering course of oral prednison e was adm ini ste red fiJr 8 weeks, starting at a dose of 1 mglkglday (Fig 3). Fi ve months afte r th e rapy was initiated, th e patie nt's symptoms improved. lie had ga in ed 21 kg, hi s CD4 lymphocyte count in creased to .5.30/JJ-L, viral load was 34,592 I !TV HNA cop ies/mL, and a repeat ches t radiograph de monstrated *From the Di vision of Infectious Diseases, Departme nt of Med icin e, Case Wes te rn Hesctve Unive rsity School of Medicine and University Hospitals of Cleveland , Ohio. Manuscript received D ecembe r 16, 1997; re,~s ion accepted March 4, 1998. Co rrespondence to: Jason W. Chien, MD, Division of Infectious Diseases, Univers ity J-los]iitals of Cleveland, Foley BuildingMailstop 5083, 11100 Euclid Ave, Clevela11d, OH 44106-5083; e111ail: jxc36@po. cwru .edu 934

FIG URE 1. Posteroanterior chest radiograph at presen tation.

marked improvement of the intrathoracic ade nopathv with nearly complete resolution of th e infiltrates. DISCUSSION

The developnlC'nt of new or increasin g lymph node e nlarge ment, cerebral tube rculomas , and contin ued symptoms such as hectic ef ver after initiation of app rop1iate an tituberculosis treatme nt has been we ll described in non-1-IIV-infccted individual s./." Th ese so-called paradoxical responses most frequ ently occur during the first few months of treatment and resol ve with continued therapy. Biopsi es of affected tissues have usually shown granulomatous inflammation with negative sm ears and cultures, and it has been postulated that the paradoxical reactions are related to hyperse nsitivity reactions to antigens released from dying tubercl e bacilli.-1 For example, lipoarabinomannan , a major component of th e cell wall of M tnhe rculosis , has been shown to induce th e expression of th e proinflammat01y cytokine tumor necrosis factor-a by human blood monocytes ..J On th e oth er hand, current unde rstanding of the immun e response in TB is that delayed-type hypersensitivity ski n test responses and their in vitro correlates, such as pmifi cd protein derivativestimulated lymphocyte blastogenesis , arc decreased in some pati ents . \Vithin 2 to 4 weeks after th e start of th erapy, tube rculin skin test reactivity and lymphocyte blastogen esis begin to improvc.-5 Therefore, such paradoxical responses are, in fact , more likely to he due to reconstitution of host immun e responses following the initi atio n of antituberculosis chemotherapy. After initial improvement in clinical symptoms and CD4 lymphocyte cou nt, our patient developed marked cervical and mediastinal lymp hadenopathy and fever. Acquired drug resistance, malabsorption , and other nontuherculous etiologies were excluded. The adenopathy was Selected Reports

F rc:URE 2. Poste roanteri or (left) am! lateral (right ) chest rad iografhs after 6 weeks of' antiretroviral and antituberc11 losis che motherapy demon strate new mediastinal anc hilar adenopathy, worsen ing of right midd le lobe infiltrate, and a new right ol wer lobe in fil trate. .... Prednisone 1

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interrupted b etween hospital qays 23 and 29 for suspected d rug fever. Note th e increase in temperature and in weight sh01tly after in itiation of'
CHEST I 114 I 3 I SEPTEMBER, 1998

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felt to represent a paradoxical response to antituberculosis treatment. In a recent preliminary report from Miami, Narita et al6 noted similar paradoxical reactions in four HIV-infected patients with TB. The reactions coincided with improved CD4 lymphocyte counts, decreases in plasma HIV load, and strongly positive purified protein derivative skin test reactions . TB and HIV infection are both characterized by immune dysfunction . TB is associated with depressed delayed-type hypersensitivity responses and other abnormalities, which are restored to normal by effective antituberculosis therapy. HIV infection is associated with a progressive reduction in CD4 lymphocytes, which are critical effector cells against intracellular pathogens. Both TB and HIV suppress CD4!fHl reactivity. 7 Effective antiretroviral therapy with nucleoside analogs and protease inhibitors result in rapid decreases in viral burden, improvement in CD4 counts within 2 to 4 weeks, and enhanced CD4 lymphocyte function. 8· 10 TB and HIV also are copathogenic in terms of generalized activation of the immune system 11 and tumor necrosis factor-a production,12 both of which increase HIV replication. Treatment with highly active antiretroviral therapy and antituberculosis therapy may lead to rapid and profound improvement in host immune responses. The transient worsening of symptoms noted after the onset of treatment may be secondary to heightened inflammatory responses against M tuberculosis or its products. Although such paradoxical reactions have not been reported widely, greater use of highly active antiretroviral therapy may increase their frequency. Physicians must be certain that any clinical deterioration is not due to drugresistant organisms, nosocomial infection, other HIVrelated malignancies or opportunistic infections, drug reactions, malabsorption, or noncompliance. When drug resistance is a strong concern, it is appropriate to add at least two additional new agents to the TB treatment regimen. Once these factors have been excluded, it is important to recognize that the phenomenon of paradoxical reactions is self-limited and management is symptomatic. Combination TB and HIV chemotherapy should be continued. REFERENCES 1 Carter EJ, Mates S. Sudden enlargement of a de ep ce1vical lymph node during and after treatm ent for pulmonary tuberculosis. Chest 1994; 106:1896-1898 2 Teoh R , Humphries MJ, O'Mahony G. Symptomatic intracranial tuberculoma developing during treatm ent of tube rculosis: a report of 10 patients and review of the literature. Q J M ed 1987; 63:449-460 3 British Thoracic Society Research Committee. Short course chemotherapy for tuberculosis of lymph nodes: a controlled trial. BMJ 1985; 290:1106-1108 4 Moreno C, Taveme J, Mehlert A, et al. Lipoarabinomannan from Mycobacterium tuberculosis induces the production of tumour necrosis factor from human and murine macrophages. Clin Exp Immunol 1989; 76:240-245 5 Rooney JJ, Crocco JA, Kramer S, et al. Further observations on tuberculin reactions in active tuberculosis. Am J M ed 1976; 60:517-522 6 Narita M, Ashkin D, Hollender ES, et al. Transient worsening of systemic signs and symptoms after antiretroviral therapy in

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patients with tuberculosis and AIDS [abstract]. Am J Respir Crit Care Med 1997; 155(part 2):A255 Zhang M,Gong J, Iyer DV, eta!. T cell cytokine responses in persons with tuberculosis and human immunodeficiency virus infection. J Clin Invest 1994; 94:2435-2442 Collier AC, Coombs RW, Schoenfeld DA, et al. Treatment of human immunodeficiency virus infection with saquinavir, zidovudine, and zalcitabine . N Eng! J M ed 1997; 334:10111017 Rouleau D, Montaner JSG, Conway B, et a!. Predictors of viral load response in a pilot open label study of stavudine (d4T) in combination with lamivudine (3TC) [abstract]. Fourth Conference on Retroviruses and Opportunistic Infection 1997; Jan 22-26:167 Lederman M, Connick E, Landay A, et a!. Partial immune reconstitution after 12 weeks of HAART (AZT, 3TC, ritonavir): preliminary results of ACTG 315 [abstract]. Fourth Conference on Retroviruses and Opportunistic Infection 1997; Jan 22-26:208 Vanharn G, Edmonds K, Qing L, e t !.a Generalized immune activation in pulmona1y tuberculosis: co-activation with HIV infection. Clin Exp Immunol 1996; 103:30-34 Wallis RS , Vjecha M, Amir-Tahmasseb M, e t a!. Influence of tube rculosis on human immunodeficie ncy virus (HIV-1 ): enhanced cytokine expression and elevated 2-microglobulin in HIV-1 associated tube rculosis . J Infect Dis 1993; 167:43-48

Intralobar Pulmonary Sequestration With Three Aberrant Arteries in a 75-YearOid Patient* Yoshio Tsunezuka, MD, PhD; and Hideo Sato, MD, PhD

A rare case of intralobular pulmonary sequestration (ILS) with three aberrant arteries occurred in a 75-year-old woman. A contrast-enhanced chest CT scan demonstrated a paraaortic, partially enhanced mass shadow and two small liner enhancements in the upper portion of the mass. A definitive diagnosis could not be rendered with a CT scan alone, but the findings suggested bronchopulmonary sequestration with multiple aberrant arteries. Surgery confirmed three fine aberrant arteries arising from the thoracic aorta and entering the left lower lobe basal segment. Judging from the patient's age and multiple aberrant arteries, the sequestrated lung appeared as if it were acquired. However, all aberrant arteries were of the elastic type histologically. This finding suggested that ILS was not an acquired condition but a congenital malformation. (CHEST 1998; 114:936-938) Key words: aberrant artery; bronchopulmonary sequestration; congenital malformation; elastic laminae Abbreviations: ILS = intralobar pulmonary sequestration Selected Reports